Volume 92, Issue 2
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



There is limited understanding of the epidemiology of meningitis among human immunodeficiency virus (HIV)-infected populations in sub-Saharan Africa. We conducted a prospective cohort study of HIV-infected adults with suspected meningitis in Uganda, to comprehensively evaluate the etiologies of meningitis. Intensive cerebrospiral fluid (CSF) testing was performed to evaluate for bacterial, viral, fungal, and mycobacterial etiologies, including neurosyphilis,16s ribosomal DNA (rDNA) polymerase chain reaction (PCR) for bacteria, Plex-ID broad viral assay, quantitative-PCR for HSV-1/2, cytomegalovirus (CMV), Epstein–Barr virus (EBV), and ; reverse transcription-PCR (RT-PCR) for Enteroviruses and arboviruses, and Xpert MTB/RIF assay. Cryptococcal meningitis accounted for 60% (188 of 314) of all causes of meningitis. Of 117 samples sent for viral PCR, 36% were EBV positive. Among cryptococcal antigen negative patients, the yield of Xpert MTB/RIF assay was 22% (8 of 36). After exclusion of cryptococcosis and bacterial meningitis, 61% (43 of 71) with an abnormal CSF profile had no definitive diagnosis. Exploration of new TB diagnostics and diagnostic algorithms for evaluation of meningitis in resource-limited settings remains needed, and implementation of cryptococcal diagnostics is critical.


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  1. WHO, 2013. Health Topics: Meningitis. Available at: http://www.who.int/topics/meningitis/en/. Accessed January 20, 2013. [Google Scholar]
  2. WHO, 2007. Standardized Treatment of Bacterial Meningitis in Africa in Epidemic and Non-Epidemic Situations. WHO/CDS/EPR/2007.3. Geneva: WHO Press. [Google Scholar]
  3. Jarvis JN, Meintjes G, Williams A, Brown Y, Crede T, Harrison TS, , 2010. Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases. BMC Infect Dis 10: 67.[Crossref] [Google Scholar]
  4. Hakim JG, Gangaidzo IT, Heyderman RS, Mielke J, Mushangi E, Taziwa A, Robertson VJ, Musvaire P, Mason PR, , 2000. Impact of HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients. AIDS 14: 14011407.[Crossref] [Google Scholar]
  5. Amuron B, Levin J, Birunghi J, Namara G, Coutinho A, Grosskurth H, Jaffar S, , 2011. Mortality in an antiretroviral therapy programme in Jinja, south-east Uganda: a prospective cohort study. AIDS Res Ther 8: 39.[Crossref] [Google Scholar]
  6. Bhagwan S, Naidoo K, , 2011. Aetiology, clinical presentation, and outcome of meningitis in patients coinfected with human immunodeficiency virus and tuberculosis. Aids Res Treat 2011: 180352. [Google Scholar]
  7. Cohen DB, Zijlstra EE, Mukaka M, Reiss M, Kamphambale S, Scholing M, Waitt PI, Neuhann F, , 2010. Diagnosis of cryptococcal and tuberculous meningitis in a resource-limited African setting. Trop Med Int Health 15: 910917.[Crossref] [Google Scholar]
  8. Siddiqi OK, Ghebremichael M, Dang X, Atadzhanov M, Kaonga P, Khoury MN, Koralnik IJ, , 2014. Molecular diagnosis of central nervous system opportunistic infections in HIV-infected Zambian adults. Clin Infect Dis 58: 17711777.[Crossref] [Google Scholar]
  9. Wall EC, Everett DB, Mukaka M, Bar-Zeev N, Feasey N, Jahn A, Moore M, van Oosterhout JJ, Pensalo P, Baguimira K, Gordon SB, Molyneux EM, Carrol ED, French N, Molyneux ME, Heyderman RS, , 2014. Bacterial meningitis in Malawian adults, adolescents, and children during the era of antiretroviral scale-up and Haemophilus influenzae type b vaccination, 2000–2012. Clin Infect Dis 58: e137e145.[Crossref] [Google Scholar]
  10. National Institute for Communicable Diseases Meiring S, Quan V, Govender N, Crowther-Gibson P, , 2012. GERMS-SA Annual Report 2012. , eds. Available at: http://www.nicd.ac.za/?page=publications&id=155. Accessed October 28, 2014.
  11. Berhe T, Melkamu Y, Amare A, , 2012. The pattern and predictors of mortality of HIV/AIDS patients with neurologic manifestation in Ethiopia: a retrospective study. AIDS Res Ther 9: 11.[Crossref] [Google Scholar]
  12. Alemu AS, Kempker RR, Tenna A, Smitson C, Berhe N, Fekade D, Blumberg HM, Aseffa A, , 2013. High prevalence of cryptococcal antigenemia among HIV-infected patients receiving antiretroviral therapy in Ethiopia. PLoS ONE 8: e58377.[Crossref] [Google Scholar]
  13. Beyene T, Woldeamanuel Y, Asrat D, Ayana G, Boulware DR, , 2013. Comparison of cryptococcal antigenemia between antiretroviral naïve and antiretroviral experienced HIV positive patients at two hospitals in Ethiopia. PLoS ONE 8: e75585.[Crossref] [Google Scholar]
  14. Afifi S, Karsany MS, Wasfy M, Pimentel G, Marfin A, Hajjeh R, , 2009. Laboratory-based surveillance for patients with acute meningitis in Sudan, 2004–2005. Eur J Clin Microbiol Infect Dis 28: 429435.[Crossref] [Google Scholar]
  15. Trachtenberg JD, Kambugu AD, McKellar M, Semitala F, Mayanja-Kizza H, Samore MH, Ronald A, Sande MA, , 2007. The medical management of central nervous system infections in Uganda and the potential impact of an algorithm-based approach to improve outcomes. Int J Infect Dis 11: 524530.[Crossref] [Google Scholar]
  16. Torok ME, Chau TT, Mai PP, Phong ND, Dung NT, Chuong LV, Lee SJ, Caws M, de Jong MD, Hien TT, Farrar JJ, , 2008. Clinical and microbiological features of HIV-associated tuberculous meningitis in Vietnamese adults. PLoS One 3: e1772.[Crossref] [Google Scholar]
  17. Kennedy DH, Fallon RJ, , 1979. Tuberculous meningitis. JAMA 241: 264268.[Crossref] [Google Scholar]
  18. Caws M, Thwaites GE, Duy PM, Tho DQ, Lan NT, Hoa DV, Chau TT, Huyen MN, Anh PT, Chau NV, Chinh TN, Stepniewska K, Farrar J, , 2007. Molecular analysis of Mycobacterium tuberculosis causing multidrug-resistant tuberculosis meningitis. Int J Tuberc Lung Dis 11: 202208. [Google Scholar]
  19. Thwaites GE, Chau TT, Stepniewska K, Phu NH, Chuong LV, Sinh DX, White NJ, Parry CM, Farrar JJ, , 2002. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Lancet 360: 12871292.[Crossref] [Google Scholar]
  20. Juan RS, Sanchez-Suarez C, Rebollo MJ, Folgueira D, Palenque E, Ortuno B, Lumbreras C, Aguado JM, , 2006. Interferon gamma quantification in cerebrospinal fluid compared with PCR for the diagnosis of tuberculous meningitis. J Neurol 253: 13231330.[Crossref] [Google Scholar]
  21. Patel VB, Singh R, Connolly C, Kasprowicz V, Ndung'u T, Dheda K, , 2011. Comparative utility of cytokine levels and quantitative RD-1-specific T cell responses for rapid immunodiagnosis of tuberculous meningitis. J Clin Microbiol 49: 39713976.[Crossref] [Google Scholar]
  22. O'Grady J, Bates M, Chilukutu L, Mzyece J, Cheelo B, Chilufya M, Mukonda L, Mumba M, Tembo J, Chomba M, Kapata N, Maeurer M, Rachow A, Clowes P, Hoelscher M, Mwaba P, Zumla A, , 2012. Evaluation of the Xpert MTB/RIF assay at a tertiary care referral hospital in a setting where tuberculosis and HIV infection are highly endemic. Clin Infect Dis 55: 11711178.[Crossref] [Google Scholar]
  23. Patel VB, Theron G, Lenders L, Matinyena B, Connolly C, Singh R, Coovadia Y, Ndung'u T, Dheda K, , 2013. Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous meningitis in a high burden setting: a prospective study. PLoS Med 10: e1001536.[Crossref] [Google Scholar]
  24. Nhu NT, Heemskerk D, Thu do DA, Chau TT, Mai NT, Nghia HD, Loc PP, Merson L, Thinh TT, Day J, Chau N, Wolbers M, Farrar J, Caws M, , 2014. Evaluation of GeneXpert MTB/RIF for diagnosis of tuberculous meningitis. J Clin Microbiol 52: 226233.[Crossref] [Google Scholar]
  25. Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A, Taseera K, Nabeta HW, Schutz C, Williams DA, Rajasingham R, Rhein J, Thienemann F, Lo MW, Nielsen K, Bergemann TL, Kambugu A, Manabe YC, Janoff EN, Bohjanen PR, Meintjes G, , 2014. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 370: 24872498.[Crossref] [Google Scholar]
  26. Bahr N, Boulware DR, Marais S, Scriven J, Wilkinson RJ, Meintjes G, , 2013. Central nervous system immune reconstitution inflammatory syndrome. Curr Infect Dis Rep 15: 583593.[Crossref] [Google Scholar]
  27. Boulware DR, Rolfes MA, Rajasingham R, von Hohenberg M, Qin Z, Taseera K, Schutz C, Kwizera R, Butler EK, Meintjes G, Muzoora C, Bischof JC, Meya DB, , 2014. Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast. Emerg Infect Dis 20: 4553.[Crossref] [Google Scholar]
  28. Blakemore R, Story E, Helb D, Kop J, Banada P, Owens MR, Chakravorty S, Jones M, Alland D, , 2010. Evaluation of the analytical performance of the Xpert MTB/RIF assay. J Clin Microbiol 48: 24952501.[Crossref] [Google Scholar]
  29. Rajasingham R, Rolfes MA, Birkenkamp KE, Meya DB, Boulware DR, , 2012. Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis. PLoS Med 9: e1001316.[Crossref] [Google Scholar]
  30. Wanyenze R, Kamya M, Liechty CA, Ronald A, Guzman DJ, Wabwire-Mangen F, Mayanja-Kizza H, Bangsberg DR, , 2006. HIV counseling and testing practices at an urban hospital in Kampala, Uganda. AIDS Behav 10: 361367.[Crossref] [Google Scholar]
  31. Meda J, Kalluvya S, Downs JA, Chofle AA, Seni J, Kidenya B, Fitzgerald DW, Peck RN, , 2014. Cryptococcal meningitis management in Tanzania with strict schedule of serial lumber punctures using intravenous tubing sets: an operational research study. J Acquir Immune Defic Syndr 66: e31e36. [Google Scholar]
  32. Hillemann D, Rusch-Gerdes S, Boehme C, Richter E, , 2011. Rapid molecular detection of extrapulmonary tuberculosis by the automated GeneXpert MTB/RIF system. J Clin Microbiol 49: 12021205.[Crossref] [Google Scholar]
  33. Zeka AN, Tasbakan S, Cavusoglu C, , 2011. Evaluation of the GeneXpert MTB/RIF assay for rapid diagnosis of tuberculosis and detection of rifampin resistance in pulmonary and extrapulmonary specimens. J Clin Microbiol 49: 41384141.[Crossref] [Google Scholar]
  34. Causse M, Ruiz P, Gutierrez-Aroca JB, Casal M, , 2011. Comparison of two molecular methods for rapid diagnosis of extrapulmonary tuberculosis. J Clin Microbiol 49: 30653067.[Crossref] [Google Scholar]
  35. Boulware DR, , 2013. Utility of the Xpert MTB/RIF assay for diagnosis of tuberculous meningitis. PLoS Med 10: e1001537.[Crossref] [Google Scholar]
  36. Alvarez-Uria G, Azcona JM, Midde M, Naik PK, Reddy S, Reddy R, , 2012. Rapid diagnosis of pulmonary and extrapulmonary tuberculosis in HIV-infected patients. comparison of LED fluorescent microscopy and the GeneXpert MTB/RIF assay in a district hospital in India. Tuberc Res Treat 2012: 932862. [Google Scholar]
  37. Tortoli E, Russo C, Piersimoni C, Mazzola E, Dal Monte P, Pascarella M, Borroni E, Mondo A, Piana F, Scarparo C, Coltella L, Lombardi G, Cirillo DM, , 2012. Clinical validation of Xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis. Eur Respir J 40: 442447.[Crossref] [Google Scholar]
  38. Vadwai V, Boehme C, Nabeta P, Shetty A, Alland D, Rodrigues C, , 2011. Xpert MTB/RIF: a new pillar in diagnosis of extrapulmonary tuberculosis? J Clin Microbiol 49: 25402545.[Crossref] [Google Scholar]
  39. Kelly MJ, Benjamin LA, Cartwright K, Ajdukiewicz KM, Cohen DB, Menyere M, Galbraith S, Guiver M, Neuhann F, Solomon T, Lalloo DG, Heyderman RS, , 2012. Epstein-Barr virus coinfection in cerebrospinal fluid is associated with increased mortality in Malawian adults with bacterial meningitis. J Infect Dis 205: 106110.[Crossref] [Google Scholar]
  40. Benjamin LA, Kelly M, Cohen D, Neuhann F, Galbraith S, Mallewa M, Hopkins M, Hart IJ, Guiver M, Lalloo DG, Heyderman RS, Solomon T, , 2013. Detection of herpes viruses in the cerebrospinal fluid of adults with suspected viral meningitis in Malawi. Infection 41: 2731.[Crossref] [Google Scholar]

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Supplementary PDF

  • Received : 21 Jul 2014
  • Accepted : 19 Sep 2014
  • Published online : 04 Feb 2015

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